This project is based upon the relatively recent realization that obesity, and especially visceral obesity, is a chronic inflammatory condition characterized by migration of high numbers of macrophages into the adipose tissue, with consequent increased local and plasma levels of cytokines. The consequences of these changes are thought to be causally linked to insulin resistance and the metabolic syndrome. In particular, high levels of inflammatory cytokines in the plasma, and especially tumor necrosis factor-1 (TNF1), have been recognized as an important risk factor for several metabolic and cardiovascular disorders, and in animal models reductions in TNF1 ameliorate many of the deleterious effects of obesity. There is compelling evidence that an important initial step along the road to obesity is an increase of TNF1 synthesis by adipose tissue, and that this in turn stimulates preadipocytes and local endothelial cells to recruit macrophages into the adipose tissue. This continues as a spiraling situation of increased inflammatory signaling molecules and mutual cross-stimulation of adipocytes and macrophages. TNF1 and other inflammatory signaling molecules eventually reach high enough levels to be detected in the plasma. Because TNF1 from adipose tissue circulates throughout the body and reaches diverse receptor populations, the role of TNF1 activity at specific sites, and at selective receptors, in the etiology of obesity and insulin resistance is not known. We have preliminary evidence that one important site of TNF1 action is in the brain, where it interacts with other signals that influence energy intake. Proposed experiments will (1) test the hypothesis that TNF1 acts in the brain to control energy homeostasis, and specifically that TNF1 action within the brain increases central insulin sensitivity while simultaneously decreasing systemic insulin sensitivity. A related hypothesis is that TNF1 is more effective in the brains of animals that have systemic insulin resistance, such as high-fat diet (HFD) induced obesity;(2) assess the relative contributions of free (unbound;soluble) TNF1 and membrane-bound TNF1 in the effects of TNF1 on energy balance;and (3) determine whether subcutaneous adipose tissue, mesenteric adipose tissue, or adipose tissue-resident macrophages are individually (or in combination) sufficient sources of TNF1 to elicit symptoms of the metabolic syndrome. Experiments will use normal (wild-type) mice and mice lacking TNF1 or its receptors or else mice lacking TACE, the enzyme that cleaves membrane-bound TNF1 to free TNF1. PUBLIC HEALTH RELEVANCE: Visceral obesity is recognized to be a chronic inflammatory condition characterized by high numbers of macrophages in adipose tissue and elevated plasma levels of cytokines such as tumor necrosis factor-1 (TNF1) that is thought to lead to insulin resistance. Proposed experiments will test the hypothesis that TNF1 acts in the brain to control food intake and systemic insulin sensitivity, and determine which form of TNF1 is critical. Experiments will use normal (wild-type) mice and mice lacking TNF1 or its receptors.